Streptococcus pneumoniae can colonize the upper respiratory tract of humans and subsequently cause mucosal infections such as sinusitis, otitis media, and pneumonia, and also invasive pneumococcal diseases (IPD) including complicated pneumonia (empyema and necrotizing pneumonia), bacteremia, and meningitis. One of the most severe complications of IPD is hemolytic uremic syndrome (HUS), which mainly occurs in children and is associated with hemolytic anemia, thrombocytopenia and acute renal failure (HUS triad). In HUS patients, pneumococcal neuraminidase cleaves N-acetylneuraminic acid (sialic acid) residues on red blood cells (RBC) leading to the exposure of the Thomsen-Friedenrich antigen (T-antigen; TA) on cells and allowing normally circulating anti-TA antibodies to react with the exposed TA to form immune complex and subsequent lysis of the cells. In a recent study, we examined the distribution of three neuraminidase genes (nanA, nanB and nanC) in pneumococcal isolates derived from HUS patients and those without. S. pneumoniae intrinsically carried nanA and nanB, while relative to 89% of the HUS isolates that harbored nanC, only 42% of the IPD isolates from the controls carried the gene. We thus speculated that NanC might contribute to the risk of developing HUS in an additive manner in the presence of NanA and NanB by increasing the overall activity of pneumococcal neuraminidases, and so was associated with the occurrence of HUS following pneumococcal infection.
Neuraminidase-producing organisms, like S. pneumoniae, acquire sialic acid by cleaving host sialo-glycoconjugates and use it as their carbon and nitrogen source. During pneumococcal infection, cleavage of sialyl linkages to expose TA in host cells might be due to a higherneuraminidase activity from NanA, NanB, or NanC or an additive effect of the three. Previously, S. pneumoniae serotype 2 (strain R6) and serotype 4 (strain TIGR4) were used to confirm α2-3 sialyl linkages specificity of the NanB and NanC produced. Recently, a report showed that NanA and NanB mutants of S. pneumoniae are deficient in adherence to three epithelial cell lines, as well as to primary nasopharyngeal cells. In the respiratory tract, distribution of α2-3 and α2-6 sialyl linkages varies depending on age, tissue and cell types; α2-3 linkages are selectively present on goblet cells and secreted mucins and α2-6 linkages on ciliated respiratory epithelial cells. Additional presence of NanC in S. pneumoniae may therefore help the pathogen to acquire more sialic acid from the respiratory tract during colonization and infection.
Detection of TA activation using peanut agglutinin (PNA) was thought to be the most appropriate test to support the diagnosis of pneumococcal HUS. Pneumococcal HUS is a well-characterized condition but continues to be under recognized. To improve the under-diagnosis and late detection of HUS, more specific laboratory tests are needed. This study adds fetuin-A as a biomarker to predict severe IPD, such as HUS and complicated pneumonia.